Predisposition to develop Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes while others offer resistance from arthritis. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to develop arthritis while DRB1*0402 provides protection. Collagen-induced arthritis (CIA) susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies similar to that in RA patients. Similar to humans, the HLA-DR4 transgenic mice develop CIA more often in females than males. In aim 1 we will investigate the mechanism of association of DR and DQ alleles with arthritis by studying immunogenicity and presentation of posttranslationally modified synovial proteins. We hypothesize that DR4 has a role in gender-bias of arthritis, where DR4 expression, presentation of antigen by various APCs and ensuing responses are different in males and females. Female sex hormone, estrogen, is involved in pathogenesis by enhancing production of peptidyl arginine deiminase (PAD) enzyme that leads to citrullination of synovial proteins. These citrullinated proteins are presented with greater efficiency by HLA-DR4 molecules leading to an autoreactive T and B cell response and disease. On the other hand, DQ8 can present native and de-amidated peptides derived from synovial proteins generating a robust autoimmune response. In aim 2 we will test role of shared epitope in protection versus susceptibility. For this aim, we will study modulation of immune response by gene complementation and epistatic interactions between DR and DQ molecules. We will use DRB1*0401 and DRB1*0402 transgenic mice to determine the mechanism of protection to understand how three amino acid difference in these molecules leads to protection by the latter. We hypothesize that antigen presentation by DQ8 molecule leads to production of high levels of pro- inflammatory IL-17 while polymorphism in DR4 gene leads to production of either pro-inflammatory or acute inflammatory cytokines. In this aim we will focus on the role of IL-17 and IFNg in susceptibility Vs protection/modulation of disease. We are generating IL-17 knockout, IFNg knockout and triple transgenic *0401/*0402/DQ8 mice for this aim. Recent literature has shown a protective/ susceptible effect of non- inherited maternal antigen (NIMA) on the development of arthritis. In aim3, we will use various matings to generate mice that have been exposed in utero to one NIMA. These mice will be evaluated for in vivo arthritis, autoantibodies and function of T and B cells. The proposed experiments will test several new, original and innovative theories on the role of MHC genes in predisposition, onset, progression, severity and modulation in arthritis. The findings would shed light on the role of MHC, immune system in health and disease and may identify new therapeutic approaches for arthritis.